The candidate, Dr. Lakshmi Devi is a Professor in the Department of Pharmacology Systems Therapeutics, Mount Sinai School of Medicine. She is currently funded by two independent grants: DA 08863 from NIDA/NIH- to study post-translational regulation of opioid receptors and NS 26880 from NINDS/NIH-to study regulation of neuropeptide biosynthesis. The long-term career goals of the candidate are to explore the contribution of opioid receptor characteristics to development of drug addiction and to identify molecules and pathways involved in this process with the intent of developing pharmacological tools to help in the prevention and/or treatment of drug abuse. Mount Sinai School of Medicine provides the intellectual environment for synergistic and collaborative interactions necessary to achieve this goal. The Senior Scientist Research and Mentorship Award will facilitate this by relieving considerable amount of teaching and administrative duties. The focus of studies in Dr. Devi's laboratory has been to explore molecular mechanisms modulating opioid receptor function. The activity of opioid receptors is modulated by multiple mechanisms. For example, the activity is modulated at the level of the receptors themselves as well as at the level of endogenous peptides (that activate the receptors). In recent years the candidate's research has focused on both these mechanisms. The studies in this application are to further explore these two mechanisms. The specific aims are: (i) to investigate signaling, maturation and regulation of 5-4 receptors by morphine administration in vivo; (ii) to study the role of heterodimerization between opioid receptors and other heptahelical receptors, and (iii) to explore the physiological involvement of recently identified non-classical processing enzymes in the regulation of opioid and other neuropeptide levels. The studies described in this grant application will provide critical information on early events that regulate opioid receptor function. Elucidation of the cellular pathways involved in modulation of receptor function is a compelling strategy for identifying appropriate pharmacological interventions for drug addiction. This Award will allow the candidate to focus on research in the field of opioid peptides and their receptors. In addition, this Award will help mentor the next generation of researchers interested in exploring novel mechanisms and identifying novel targets for the treatment of drug abuse disorders. PUBLIC HEALTH RELEVANCE: The studies described in this application use a combination of classical techniques with novel tools and state-of-the art technology to characterize the role of heterodimerization in modulating receptor signaling, maturation/upregulation, to explore the physiological significance of heterodimerization in vivo and to explore the role of non-classical processing enzymes in the generation of opioid peptides. These studies will open new avenues and/or targets for intervention in drug abuse and addiction.